JPH06321776A - Antiinflammatory agent - Google Patents
Antiinflammatory agentInfo
- Publication number
- JPH06321776A JPH06321776A JP6032686A JP3268694A JPH06321776A JP H06321776 A JPH06321776 A JP H06321776A JP 6032686 A JP6032686 A JP 6032686A JP 3268694 A JP3268694 A JP 3268694A JP H06321776 A JPH06321776 A JP H06321776A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- sodium
- reaction
- potassium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002260 anti-inflammatory agent Substances 0.000 title claims abstract description 9
- 229940121363 anti-inflammatory agent Drugs 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 230000003266 anti-allergic effect Effects 0.000 abstract description 4
- 230000003356 anti-rheumatic effect Effects 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 210000002683 foot Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 208000009386 Experimental Arthritis Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- -1 alkali metal salt Chemical class 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 230000001754 anti-pyretic effect Effects 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 235000010418 carrageenan Nutrition 0.000 description 4
- 229920001525 carrageenan Polymers 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- KJVBJICWGQIMOZ-UHFFFAOYSA-N 2-fluoro-5-nitroaniline Chemical compound NC1=CC([N+]([O-])=O)=CC=C1F KJVBJICWGQIMOZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000011694 lewis rat Methods 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- UDWKPLLNAQEMPI-UHFFFAOYSA-N n-(2-fluoro-5-nitrophenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC([N+]([O-])=O)=CC=C1F UDWKPLLNAQEMPI-UHFFFAOYSA-N 0.000 description 2
- IGRAVAFHBHAIRV-UHFFFAOYSA-N n-(5-amino-2-phenoxyphenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(N)=CC=C1OC1=CC=CC=C1 IGRAVAFHBHAIRV-UHFFFAOYSA-N 0.000 description 2
- KRCSVRAAQUDCPY-UHFFFAOYSA-N n-(5-amino-4-nitro-2-phenoxyphenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(N)=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 KRCSVRAAQUDCPY-UHFFFAOYSA-N 0.000 description 2
- FUBBAWCFVISWIE-UHFFFAOYSA-N n-(5-nitro-2-phenoxyphenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC([N+]([O-])=O)=CC=C1OC1=CC=CC=C1 FUBBAWCFVISWIE-UHFFFAOYSA-N 0.000 description 2
- 230000000802 nitrating effect Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- JYENLFHVUQDQQB-UHFFFAOYSA-M N.[Na+].[SH-].Cl Chemical compound N.[Na+].[SH-].Cl JYENLFHVUQDQQB-UHFFFAOYSA-M 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000019189 interleukin-1 beta production Effects 0.000 description 1
- 230000018276 interleukin-1 production Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- 229940080428 lactose 200 mg Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- QHDUJTCUPWHNPK-UHFFFAOYSA-N methyl 7-methoxy-2h-indazole-3-carboxylate Chemical compound COC1=CC=CC2=C(C(=O)OC)NN=C21 QHDUJTCUPWHNPK-UHFFFAOYSA-N 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- YEENEYXBHNNNGV-XEHWZWQGSA-M sodium;3-acetamido-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoate;(2r,3r,4s,5s,6r)-2-[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound [Na+].CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I.O[C@H]1[C@H](O)[C@@H](CO)O[C@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 YEENEYXBHNNNGV-XEHWZWQGSA-M 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は、抗炎症作用、解熱作
用、鎮痛作用、坑リウマチ作用および抗アレルギー作用
を有する5−アミノ−2−フェノキシスルホンアニリド
化合物を有効成分として含有することを特徴とする抗炎
症剤に関する。The present invention is characterized by containing a 5-amino-2-phenoxysulfonanilide compound having an anti-inflammatory action, antipyretic action, analgesic action, antirheumatic action and antiallergic action as an active ingredient. Anti-inflammatory drug.
【0002】[0002]
【従来の技術】2−フェノキシスルホンアニリド化合物
は種々の化合物が知られているが、このうち本発明化合
物に構造の近いものとしては米国特許第3,840,5
97号明細書が知られている。Various compounds are known as 2-phenoxysulfoneanilide compounds. Among them, the compound having a structure similar to that of the compound of the present invention is disclosed in US Pat. No. 3,840,5.
No. 97 is known.
【0003】[0003]
【発明が解決しようとする課題】しかしながら、前記の
明細書に記載のある化合物は薬効が十分でなかった。However, some of the compounds described in the above specification have not been sufficiently effective.
【0004】本発明の目的は、抗炎症作用、解熱作用、
鎮痛作用、坑リウマチ作用および抗アレルギー作用を有
する優れた薬剤を提供することにある。The objects of the present invention are anti-inflammatory action, antipyretic action,
It is intended to provide an excellent drug having an analgesic action, an antirheumatic action and an antiallergic action.
【0005】[0005]
【課題を解決するための手段】本発明者らは、上記課題
の解決を目的に鋭意検討した結果、下記に表される5−
アミノ−2−フェノキシスルホンアニリド化合物を有効
成分として含有する抗炎症剤が目的を達成できることを
見い出し、本発明を完成した。Means for Solving the Problems As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have shown the following 5-
The inventors have found that an anti-inflammatory agent containing an amino-2-phenoxysulfoneanilide compound as an active ingredient can achieve the object, and completed the present invention.
【0006】すなわち、本発明は、式(I)That is, the present invention provides the formula (I)
【0007】 [0007]
【0008】で表される5−アミノ−2−フェノキシス
ルホンアニリド化合物およびその塩を有効成分として含
有することを特徴とする抗炎症剤である。An anti-inflammatory agent comprising a 5-amino-2-phenoxysulfoneanilide compound represented by and a salt thereof as an active ingredient.
【0009】本発明において、塩とはナトリウム、カリ
ウムなどとのアルカリ金属塩、カルシウム、マグネシウ
ムなどとのアルカリ土類金属塩、アンモニウム塩及びメ
チルアミン、エチルアミン、ブチルアミン、ジメチルア
ミン、ジエチルアミン、トリエチルアミン、トリブチル
アミン、エタノールアミン、ピリジン、リジン、アルギ
ニンなどの有機塩基との塩である。In the present invention, the salt is an alkali metal salt such as sodium and potassium, an alkaline earth metal salt such as calcium and magnesium, an ammonium salt and methylamine, ethylamine, butylamine, dimethylamine, diethylamine, triethylamine, triethylamine and triethylamine. It is a salt with an organic base such as butylamine, ethanolamine, pyridine, lysine and arginine.
【0010】本発明の抗炎症剤の有効成分である式
(I)の化合物は、例えば、下記に示す(a)〜(f)
の製造工程により得ることができる。The compounds of the formula (I) which are the active ingredients of the anti-inflammatory agent of the present invention include, for example, the following (a) to (f).
It can be obtained by the manufacturing process of.
【0011】(a)まず、2−フルオロ−5−ニトロア
ニリンに、メタンスルホン酸またはその反応性誘導体
(例えば、酸ハロゲン化物、酸無水物など)を反応させ
ることにより、式(II)(A) First, 2-fluoro-5-nitroaniline is reacted with methanesulfonic acid or a reactive derivative thereof (for example, an acid halide, an acid anhydride, etc.) to give a compound of formula (II).
【0012】 [0012]
【0013】で表される化合物を得ることができる。A compound represented by can be obtained.
【0014】本反応においてメタンスルホン酸を使用す
る場合には、N,N’−ジシクロヘキシルカルボジイミ
ドなどの縮合剤の存在下に行うのが好ましい。また、反
応性誘導体を使用する場合には塩基存在下で行うのが好
ましく、塩基としては水酸化リチウム、水酸化ナトリウ
ム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、
炭酸水素ナトリウム、炭酸水素カリウムなどの無機塩基
またはトリエチルアミン、トリ−n−ブチルアミン、
1,5−ジアザビシクロ[4.3.0]−5−ノネン、
1,8−ジアザビシクロ[5.4.0]−7−ウンデセ
ン、4−メチルモルホリン、1−メチルピペリジン、ピ
リジン、N,N−ジメチルアミノピリジンなどの有機塩
基が挙げられる。When methanesulfonic acid is used in this reaction, it is preferably carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide. When using a reactive derivative, it is preferably carried out in the presence of a base, and as the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate or triethylamine, tri-n-butylamine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Examples of the organic base include 1,8-diazabicyclo [5.4.0] -7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, and N, N-dimethylaminopyridine.
【0015】本反応は、通常溶媒中で行われ、溶媒とし
てはジクロロメタン、クロロホルム、酢酸エチル、ジオ
キサン、テトラヒドロフラン、エチルエーテル、ベンゼ
ン、トルエン、キシレン、アセトン、アセトニトリル、
水、ピリジン、N,N−ジメチルホルムアミド、ジメチ
ルスルホキシドなどが挙げられる。This reaction is usually carried out in a solvent, and as the solvent, dichloromethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran, ethyl ether, benzene, toluene, xylene, acetone, acetonitrile,
Water, pyridine, N, N-dimethylformamide, dimethylsulfoxide and the like can be mentioned.
【0016】(b)次に、式(II)の化合物にフェノ
ールを塩基存在下、反応させることにより、式(II
I)(B) Next, by reacting the compound of formula (II) with phenol in the presence of a base, the compound of formula (II)
I)
【0017】 [0017]
【0018】で表される化合物を得ることができる。A compound represented by can be obtained.
【0019】本反応における塩基としては水酸化リチウ
ム、水酸化ナトリウム、水酸化カリウムなどのアルカリ
金属水酸化物、炭酸ナトリウム、炭酸カリウムなどのア
ルカリ金属炭酸塩、炭酸水素ナトリウム、炭酸水素カリ
ウムなどのアルカリ金属炭酸水素塩、水素化ナトリウ
ム、水素化カリウムなどのアルカリ金属水素化物、金属
ナトリウム、ナトリウムアミドなどの無機塩基またはト
リエチルアミン、トリ−n−ブチルアミン、1,5−ジ
アザビシクロ[4.3.0]−5−ノネン、1,8−ジ
アザビシクロ[5.4.0]−7−ウンデセン、ピリジ
ン、N,N−ジメチルアミノピリジンなどの有機塩基な
どが挙げられる。Examples of the base in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal hydrides such as metal hydrogen carbonate, sodium hydride and potassium hydride, inorganic bases such as metal sodium and sodium amide, or triethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0]- Examples thereof include organic bases such as 5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, and N, N-dimethylaminopyridine.
【0020】本反応は、無溶媒またはジオキサン、テト
ラヒドロフラン、エチルエーテル、石油エーテル、n−
ヘキサン、シクロヘキサン、ベンゼン、トルエン、キシ
レン、ピリジン、N,N−ジメチルホルムアミド、ジメ
チルスルホキシド、ジクロロメタン、クロロホルム、水
などの溶媒を任意に選択して行うことができる。This reaction is solvent-free or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-
A solvent such as hexane, cyclohexane, benzene, toluene, xylene, pyridine, N, N-dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform, and water can be arbitrarily selected and used.
【0021】本反応においては、ヨウ化カリウム、トリ
ス〔2―(2―メトキシエトキシ)エチル〕アミン、テ
トラ−n−ブチルアンモニウムクロリド、ベンジルトリ
エチルアンモニウムクロリド、ベンジルトリエチルアン
モニウムブロミドなどの4級アンモニウム塩、18−ク
ラウン−6 エーテルなどのクラウンエーテルなどを加
えることにより反応を加速することもできる。In this reaction, quaternary ammonium salts such as potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, benzyltriethylammonium chloride and benzyltriethylammonium bromide, The reaction can also be accelerated by adding a crown ether such as 18-crown-6 ether.
【0022】(c)次いで、式(III)の化合物のニ
トロ基を還元することにより、式(IV)(C) Then, the nitro group of the compound of formula (III) is reduced to give a compound of formula (IV)
【0023】 [0023]
【0024】で表される化合物を得ることができる。The compound represented by can be obtained.
【0025】還元はニトロ基を還元してアミノ基とする
通常の還元方法でよく、例えばパラジウム−炭素、ラネ
ーニッケル、白金などを触媒として用いる接触還元、鉄
や錫を用いる還元、硫化ナトリウム−塩化アンモニウム
を用いる還元、水素化ホウ素ナトリウム、水素化リチウ
ムアルミニウムなどを用いる還元などが挙げられる。The reduction may be carried out by a conventional reduction method in which a nitro group is reduced to an amino group. For example, catalytic reduction using palladium-carbon, Raney nickel, platinum or the like as a catalyst, reduction using iron or tin, sodium sulfide-ammonium chloride. And reduction using sodium borohydride, lithium aluminum hydride and the like.
【0026】本反応に用いる溶媒としては、還元方法に
より任意に選択すればよく、一般的にはメタノール、エ
タノール、n−プロパノールなどのアルコール、水、酢
酸、酢酸エチル、ジオキサン、テトラヒドロフラン、ア
セトニトリルなどが挙げられる。The solvent used in this reaction may be arbitrarily selected according to the reduction method, and generally, alcohols such as methanol, ethanol and n-propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile and the like are used. Can be mentioned.
【0027】(d)次いで、式(IV)の化合物と式
(V) Cl−CO−R (V) (式中、Rは炭素原子数1〜5個のアルキル基、炭素原
子数1〜5個のアルコキシ基または炭素原子数2〜6個
のアルコキシカルボニル基を示す。)または式(VI) (R−CO)2O (VI) (式中、Rは炭素原子数1〜5個のアルキル基、炭素原
子数1〜5個のアルコキシ基または炭素原子数2〜6個
のアルコキシカルボニル基を示す。)で表される化合物
を反応させることにより、式(VII)(D) Next, the compound of formula (IV) and the formula (V) Cl-CO-R (V) (wherein R is an alkyl group having 1 to 5 carbon atoms, and 1 to 5 carbon atoms). Represents an alkoxy group or an alkoxycarbonyl group having 2 to 6 carbon atoms) or a formula (VI) (R-CO) 2O (VI) (In the formula, R is an alkyl group having 1 to 5 carbon atoms. Represents an alkoxy group having 1 to 5 carbon atoms or an alkoxycarbonyl group having 2 to 6 carbon atoms), to give a compound of formula (VII)
【0028】 [0028]
【0029】(式中、Rは前記と同意義である。)で表
される化合物を得ることができる。A compound represented by the formula (wherein R has the same meaning as defined above) can be obtained.
【0030】本反応は塩基存在化に行うのが好ましく、
塩基としては水酸化リチウム、水酸化ナトリウム、水酸
化カリウムなどのアルカリ金属水酸化物、炭酸ナトリウ
ム、炭酸カリウムなどのアルカリ金属炭酸塩、炭酸水素
ナトリウム、炭酸水素カリウムなどのアルカリ金属炭酸
水素塩、水素化ナトリウム、水素化カリウムなどのアル
カリ金属水素化物、金属ナトリウム、ナトリウムアミド
などの無機塩基またはトリエチルアミン、トリ−n−ブ
チルアミン、1,5−ジアザビシクロ[4.3.0]−
5−ノネン、1,8−ジアザビシクロ[5.4.0]−
7−ウンデセン、ピリジン、N,N−ジメチルアミノピ
リジンなどの有機塩基などが挙げられる。This reaction is preferably carried out in the presence of a base,
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and hydrogen. Alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium metal and sodium amide, or triethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0]-
5-nonene, 1,8-diazabicyclo [5.4.0]-
Organic bases such as 7-undecene, pyridine, N, N-dimethylaminopyridine and the like can be mentioned.
【0031】本反応は、無溶媒またはジオキサン、テト
ラヒドロフラン、エチルエーテル、石油エーテル、n−
ヘキサン、シクロヘキサン、ベンゼン、トルエン、キシ
レン、クロロベンゼン、ピリジン、酢酸エチル、アセト
ニトリル、N,N−ジメチルホルムアミド、ジメチルス
ルホキシド、ジクロロメタン、クロロホルム、水などの
溶媒を任意に選択して行うことができる。This reaction is solvent-free or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-
Solvents such as hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform and water can be arbitrarily selected and used.
【0032】(e)次いで、式(VII)の化合物を硝
酸または硝酸塩などのニトロ化剤を用いてニトロ化する
ことにより、式(VIII)(E) The compound of formula (VII) is then nitrated with a nitrating agent such as nitric acid or a nitrate to give a compound of formula (VIII)
【0033】 [0033]
【0034】(式中、Rは前記と同意義である。)で表
される化合物を得ることができる。A compound represented by the formula (wherein R has the same meaning as defined above) can be obtained.
【0035】ニトロ化反応における硝酸塩としては硝酸
ナトリウム、硝酸カリウム、硝酸鉄、硝酸ウレアなどを
用いることができ、使用する溶媒としてはニトロ化剤に
応じて任意に選択するのが好ましく、酢酸、無水酢酸、
トリフルオロ酢酸、硫酸、ジクロロメタン、クロロホル
ム、ベンゼン、ジオキサン、エタノールなどが挙げられ
る。As the nitrate in the nitration reaction, sodium nitrate, potassium nitrate, iron nitrate, urea nitrate or the like can be used, and the solvent to be used is preferably selected according to the nitrating agent, and acetic acid or acetic anhydride is used. ,
Examples include trifluoroacetic acid, sulfuric acid, dichloromethane, chloroform, benzene, dioxane, ethanol and the like.
【0036】(f)最後に、式(VIII)の化合物を
加水分解することにより、本発明の式(I)の化合物を
得ることができる。(F) Finally, the compound of formula (VIII) of the present invention can be obtained by hydrolyzing the compound of formula (VIII).
【0037】本反応における加水分解は、塩基性条件あ
るいは酸性条件における通常のアミドの加水分解方法で
あり、例えば塩基性条件としては水酸化リチウム、水酸
化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸
カリウム、ナトリウムメトキシド、ナトリウムエトキシ
ド、t−ブトキシカリウムなどを使用する方法、また、
酸性条件としては塩酸、臭化水素酸、硫酸などを用いる
方法が挙げられる。Hydrolysis in this reaction is a usual amide hydrolysis method under basic or acidic conditions. For example, basic conditions include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. , Sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.,
Examples of the acidic condition include a method using hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
【0038】本反応で使用する溶媒は、水、メタノー
ル、エタノール、プロパノール、t−ブタノール、テト
ラヒドロフラン、ジオキサン、ベンゼン、トルエン、キ
シレン、クロロベンゼン、N,N−ジメチルホルムアミ
ド、ジメチルスルホキシド、蟻酸、酢酸などが挙げられ
るが、加水分解の条件により適宜選択するのが好まし
い。The solvent used in this reaction includes water, methanol, ethanol, propanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like. Although it can be mentioned, it is preferable to select appropriately depending on the hydrolysis conditions.
【0039】本発明の化合物は、経口または非経口的に
慣用の投与剤型で投与することができる。これらは、例
えば錠剤、粉剤、顆粒剤、散剤、カプセル剤、液剤、乳
剤、懸濁剤、注射剤などであり、いずれも通常の方法に
より製造することができる。人に対して抗炎症剤、解熱
剤、鎮痛剤および抗アレルギー剤として用いる場合、そ
の投与量は、年齢、体重、症状、投与経路、投与回数な
どによって異なるが、通常1日当り5〜1000mgで
ある。The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. These include, for example, tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, injections and the like, all of which can be manufactured by a usual method. When used as an anti-inflammatory agent, antipyretic agent, analgesic agent and antiallergic agent for humans, the dose is usually 5 to 1000 mg per day, although it varies depending on age, weight, symptoms, administration route, number of administrations and the like.
【0040】[0040]
【発明の効果】本発明の有効成分である化合物は、強い
抗炎症作用、解熱作用、鎮痛作用、抗アレルギー作用お
よび坑リウマチ作用などを示し、消化管障害などの副作
用が少ないため、本発明は抗炎症剤、解熱剤、鎮痛剤、
坑リウマチ剤および抗アレルギー剤として有用である。The compound which is the active ingredient of the present invention exhibits strong anti-inflammatory action, antipyretic action, analgesic action, antiallergic action and antirheumatic action, and has few side effects such as digestive tract disorders. Anti-inflammatory, antipyretic, analgesic,
It is useful as an antirheumatic agent and an antiallergic agent.
【0041】[0041]
【実施例】次に、製造例、実施例および試験例を挙げ本
発明を更に詳細に説明する。EXAMPLES Next, the present invention will be described in more detail with reference to production examples, examples and test examples.
【0042】製造例1 (1)2−フルオロ−5−ニトロアニリン52.1gを
含むピリジン334ml溶液に、氷冷下、メタンスルホ
ニルクロリド42.1gを加え、室温で7時間攪拌し
た。反応液に水を加え、析出物を瀘取後、粗結晶をエタ
ノールで再結晶して淡黄色針状晶のN−(2−フルオロ
−5−ニトロフェニル)メタンスルホンアミド56.9
gを得た。Production Example 1 (1) To a 334 ml solution of pyridine containing 52.1 g of 2-fluoro-5-nitroaniline, 42.1 g of methanesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was filtered, and the crude crystals were recrystallized from ethanol to give pale yellow needle crystals of N- (2-fluoro-5-nitrophenyl) methanesulfonamide 56.9.
g was obtained.
【0043】m.p.162.5〜163.5℃M. p. 162.5-163.5 ° C
【0044】(2)フェノール73.5gおよび水酸化
ナトリウム31.2gを含む250ml水溶液に、N−
(2−フルオロ−5−ニトロフェニル)メタンスルホン
アミド50.0gを加え、5時間還流後、反応液を氷冷
し、撹拌下、36%塩酸50ml、エタノール200m
lを順に加えた。析出物を瀘取後、水、エタノールの順
で洗浄し、風乾して黄色プリズム晶のN−(5−ニトロ
−2−フェノキシフェニル)メタンスルホンアミド5
2.2gを得た。(2) To a 250 ml aqueous solution containing 73.5 g of phenol and 31.2 g of sodium hydroxide, N-
(2-Fluoro-5-nitrophenyl) methanesulfonamide (50.0 g) was added and the mixture was refluxed for 5 hours. The reaction mixture was ice-cooled, 36% hydrochloric acid (50 ml) and ethanol (200 m) were stirred.
1 were added in order. The precipitate was filtered, washed with water and ethanol in this order, and dried in air to obtain yellow prism crystals of N- (5-nitro-2-phenoxyphenyl) methanesulfonamide 5
2.2 g was obtained.
【0045】m.p.112〜113.5℃M. p. 112-113.5 ° C
【0046】(3)N−(5−ニトロ−2−フェノキシ
フェニル)メタンスルホンアミド52.1gに塩化アン
モニウム2.7gを含む51ml水溶液を加え、80℃
に加熱撹拌下、鉄粉42.5gを加え、2時間撹拌し
た。反応物を50℃まで冷却後、酢酸エチルおよび水を
加え、酢酸エチルで抽出した。有機層を水、飽和食塩水
の順で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒
を留去後、残渣をエタノールで再結晶してN−(5−ア
ミノ−2−フェノキシフェニル)メタンスルホンアミド
29.6gを得た。(3) A 51 ml aqueous solution containing 2.7 g of ammonium chloride was added to 52.1 g of N- (5-nitro-2-phenoxyphenyl) methanesulfonamide, and the mixture was heated at 80 ° C.
With heating and stirring, 42.5 g of iron powder was added to the above and stirred for 2 hours. The reaction mixture was cooled to 50 ° C, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 29.6 g of N- (5-amino-2-phenoxyphenyl) methanesulfonamide.
【0047】m.p.111.5〜113.5℃M. p. 111.5-113.5 ° C
【0048】(4)オキサリルクロリド13.7gを含
むジクロロメタン180ml溶液に氷冷下、n−ペンタ
ノール9.5g次いでピリジン8.5gを加え、5分間
撹拌した。反応液を−78℃に冷却下、N−(5−アミ
ノ−2−フェノキシフェニル)メタンスルホンアミド2
0.0gおよびピリジン8.5gを含むジクロロメタン
70ml溶液を加え、室温で10分間撹拌した。反応液
に水を加え、ジクロロメタンで抽出後、有機層を水、3
規定塩酸、飽和食塩水の順で洗浄し、無水硫酸マグネシ
ウムで乾燥した。溶媒を留去後、残渣をエタノールで再
結晶して、無色結晶のN−[5−(n−ペンチル)オキ
サリルアミノ−2−フェノキシフェニル]メタンスルホ
ンアミド17.2gを得た。(4) To 180 ml of a dichloromethane solution containing 13.7 g of oxalyl chloride, 9.5 g of n-pentanol and 8.5 g of pyridine were added under ice cooling, and the mixture was stirred for 5 minutes. The reaction solution was cooled to -78 ° C under N- (5-amino-2-phenoxyphenyl) methanesulfonamide 2
A 70 ml solution of dichloromethane containing 0.0 g and 8.5 g of pyridine was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution and extracted with dichloromethane.
The mixture was washed with normal hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 17.2 g of colorless crystals of N- [5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide.
【0049】m.p.164〜165℃M. p. 164-165 ° C
【0050】(5)N−[5−(n−ペンチル)オキサ
リルアミノ−2−フェノキシフェニル]メタンスルホン
アミド17.1gを含む酢酸60ml溶液に、90℃で
加熱攪拌下、60%硝酸2.7gを加え、10分間攪拌
した。反応液を室温に戻し、水を加え、析出物を瀘取
後、エタノールで再結晶して黄色針状晶のN−[4−ニ
トロ−5−(n−ペンチル)オキサリルアミノ−2−フ
ェノキシフェニル]メタンスルホンアミド11.5gを
得た。(5) To 60 ml of acetic acid solution containing 17.1 g of N- [5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide, 2.7 g of 60% nitric acid was added with heating and stirring at 90 ° C. Was added and stirred for 10 minutes. The reaction solution was returned to room temperature, water was added, the precipitate was collected by filtration, and recrystallized from ethanol to give yellow needle crystals of N- [4-nitro-5- (n-pentyl) oxalylamino-2-phenoxyphenyl. ] 11.5 g of methanesulfonamide was obtained.
【0051】m.p.123.5〜125.5℃M. p. 123.5-125.5 ° C
【0052】(6)N−[4−ニトロ−5−(n−ペン
チル)オキサリルアミノ−2−フェノキシフェニル]メ
タンスルホンアミド2.5gを含むテトラヒドロフラン
25ml溶液に室温で10%水酸化ナトリウム水溶液2
5mlを加え、10分間撹拌した。反応液に3規定塩酸
を加え中和した後、酢酸エチルで抽出後、有機層を水、
飽和食塩水の順で洗浄し、無水硫酸マグネシウムで乾燥
した。溶媒を留去後、残渣をアセトン−n−ヘキサンで
再結晶して、橙色針状晶のN−(5−アミノ−4−ニト
ロ−2−フェノキシフェニル)メタンスルホンアミド
1.6gを得た。(6) A 25% solution of N- [4-nitro-5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide in 25 ml of tetrahydrofuran at room temperature containing 10% aqueous sodium hydroxide solution 2
5 ml was added and stirred for 10 minutes. The reaction mixture was neutralized with 3N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water.
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from acetone-n-hexane to obtain 1.6 g of orange needle crystals of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide.
【0053】m.p.175〜176℃M. p. 175-176 ° C
【0054】実施例1 錠剤;1錠中に下記の成分を有する。Example 1 Tablet: Each tablet contains the following ingredients.
【0055】 式(I)の化合物 50mg 乳糖 68mg 結晶セルロース 50mg コーンスターチ 10mg カルボキシメチルセルロースカルシウム 10mg ステアリン酸マグネシウム 2mg ────────────────────────── 計 190mgCompound of Formula (I) 50 mg Lactose 68 mg Crystalline Cellulose 50 mg Corn Starch 10 mg Carboxymethyl Cellulose Calcium 10 mg Magnesium Stearate 2 mg ────────────────────────── ─ 190 mg in total
【0056】実施例2 カプセル剤;1カプセル中に下記の成分を有する。Example 2 Capsule; The following ingredients are contained in one capsule.
【0057】 式(I)の化合物 50mg 乳糖 36mg 結晶セルロース 40mg コーンスターチ 50mg ステアリン酸マグネシウム 4mg ────────────────────────── 計 180mgCompound of formula (I) 50 mg Lactose 36 mg Crystalline cellulose 40 mg Corn starch 50 mg Magnesium stearate 4 mg ─────────────────────────── Total 180 mg
【0058】実施例3 顆粒剤;1包中に下記の成分を有する。Example 3 Granule; The following ingredients are contained in one package.
【0059】 式(I)の化合物 50mg 乳糖 200mg 結晶セルロース 100mg コーンスターチ 100mg カルボキシメチルセルロースカルシウム 35mg ヒドロキシプロピルセルロース 15mg ────────────────────────── 計 500Compound of Formula (I) 50 mg Lactose 200 mg Crystalline Cellulose 100 mg Corn Starch 100 mg Carboxymethyl Cellulose Calcium 35 mg Hydroxypropyl Cellulose 15 mg ────────────────────────── ─ 500
【0060】試験例1〔カラゲニン足浮腫抑制試験〕 カラゲニン足浮腫抑制試験はウインターらの方法[Pr
oc.Soc.Exp.Biol.Med.第111
巻、第544頁(1962年)]に準拠して行った。Test Example 1 [Carrageenin paw edema inhibitory test] The carrageenin paw edema inhibitory test was carried out by the method of Winter et al. [Pr.
oc. Soc. Exp. Biol. Med. 111th
Vol. 544 (1962)].
【0061】ウイスター系ラット(1群6匹)を用い、
5%アラビアゴム水溶液に懸濁した検体[本発明化合物
(a)および対照薬(b)]を体重100g当り1ml
の投与量で経口投与した。1時間後、1%カラゲニンを
左肢足蹠に0.1ml皮下投与した。カラゲニン投与3
時間後、足容積を測定し、その浮腫抑制率(%)を求め
て抗炎症作用を調べた。Using Wistar rats (6 rats per group),
1 ml of a sample [the compound of the present invention (a) and a control drug (b)] suspended in a 5% aqueous solution of gum arabic per 100 g of body weight
Orally. One hour later, 0.1% of carrageenin was subcutaneously administered to the foot pad of the left limb. Carrageenin administration 3
After a lapse of time, the paw volume was measured, and the anti-inflammatory effect was investigated by determining the edema inhibition rate (%).
【0062】尚、検体の投与量は0.3mg/kgとし
た。The dose of the sample was 0.3 mg / kg.
【0063】試験例2〔アジュバント関節炎(治療)試
験〕 アジュバント関節炎(治療)試験は、ウインターらの方
法[Arthritis Rheum.、第12巻、第
472頁(1969年)]に準拠して行った。Test Example 2 [Adjuvant arthritis (treatment) test] The adjuvant arthritis (treatment) test is carried out by the method of Winter et al. [Arthritis Rheum. , Vol. 12, p. 472 (1969)].
【0064】ルイス系ラット(1群7匹)の左肢足蹠
に、流動パラフィンに懸濁した0.7%マイコバクテリ
ウム ツベルクローシスを皮下注射してアジュバント関
節炎を惹起した。アジュバント投与15〜18日間後、
十分発症した関節炎ラットを用い、5%アラビアゴム水
溶液に懸濁した検体[本発明化合物(a)および対照薬
(b)]を体重100g当り1mlの投与量で1日1回
4日間経口投与した。Adjuvant arthritis was induced by subcutaneously injecting 0.7% Mycobacterium tuberculosis suspended in liquid paraffin into the left foot pad of Lewis rats (1 group: 7 rats). 15-18 days after administration of adjuvant,
Using well-developed arthritic rats, the specimens [the compound of the present invention (a) and the control drug (b)] suspended in a 5% aqueous solution of gum arabic were orally administered once a day for 4 days at a dose of 1 ml per 100 g of body weight. .
【0065】最終投与の翌日足容積を測定し、その腫脹
抑制率(%)を求めて治療効果を調べた。検体の投与用
量は0.2mg/kgとした。On the day after the final administration, the paw volume was measured, and the swelling suppression rate (%) was determined to examine the therapeutic effect. The administration dose of the sample was 0.2 mg / kg.
【0066】試験例3〔アジュバント関節炎(疼痛)試
験〕 アジュバント関節炎(疼痛)試験は葛野らの方法[Ch
em.Pharm.Bull.、第23巻、第6号、第
1184頁(1975年)]に準拠して行った。Test Example 3 [Adjuvant arthritis (pain) test] Adjuvant arthritis (pain) test is carried out by the method of Kazuno et al. [Ch
em. Pharm. Bull. , Vol. 23, No. 6, p. 1184 (1975)].
【0067】ルイス系ラット(1群10匹)の左肢足蹠
に、流動パラフィンに懸濁した0.7%マイコバクテリ
ウム ツベルクローシスを皮下注射してアジュバント関
節炎を惹起した。アジュバント投与15〜18日間後、
右後肢足関節の屈曲伸展刺激疼痛に対して鳴啼反応を示
す関節炎ラットを用い、5%アラビアゴム水溶液に懸濁
した検体[本発明化合物(a)および対照薬(b)]を
体重100g当り1mlの投与量で経口投与した。投与
後5時間目まで経時的に鳴啼反応の有無を測定し、その
抑制率(%)を求めて鎮痛作用を調べた。検体の投与用
量は1.0mg/kgとした。Adjuvant arthritis was induced by subcutaneously injecting 0.7% Mycobacterium tuberculosis suspended in liquid paraffin into the foot pads of Lewis rats (10 rats per group). 15-18 days after administration of adjuvant,
Using arthritis rats showing a squealing reaction to flexion-extension stimulating pain of the right hind ankle joint, a sample [the present compound (a) and a control drug (b)] suspended in a 5% aqueous solution of gum arabic was used per 100 g of body weight. It was orally administered at a dose of 1 ml. The presence or absence of a squeaking reaction was measured with time up to 5 hours after the administration, and the inhibition rate (%) was determined to examine the analgesic effect. The administration dose of the sample was 1.0 mg / kg.
【0068】以上、試験例1〜3の結果をまとめて表1
に示した。The results of Test Examples 1 to 3 are summarized above in Table 1.
It was shown to.
【0069】[0069]
【表1】 [Table 1]
【0070】本発明化合物(a);N―(5―アミノ―
4―ニトロ―2―フェノキシフェニル)メタンスルホン
アミド 対照薬(b);N―(4―ニトロ―2―フェノキシフェ
ニル)メタンスルホンアミドCompound (a) of the present invention; N- (5-amino-
4-Nitro-2-phenoxyphenyl) methanesulfonamide Control drug (b); N- (4-nitro-2-phenoxyphenyl) methanesulfonamide
【0071】試験例4[IL−1産生抑制試験] ヘパリン処理した正常人末梢血を無菌条件下でリンホプ
レップ(第一製薬)に重層して赤血球を除去後、細胞を
牛胎児血清10%、ペニシリン100U/ml、ストレ
プトマイシン100U/ml、ヘペス緩衝液10mMお
よびL−グルタミン2mMを加えたRPMI−1640
培地(ギブコ社)に浮遊させて細胞数を2×106ce
lls/mlに調製した。Test Example 4 [IL-1 Production Inhibition Test] Heparin-treated normal human peripheral blood was layered on Lymphoprep (Daiichi Pharmaceutical Co., Ltd.) under sterile conditions to remove red blood cells, and then the cells were fetal bovine serum 10% and penicillin. RPMI-1640 with 100 U / ml, streptomycin 100 U / ml, Hepes buffer 10 mM and L-glutamine 2 mM.
Suspend in medium (Gibco) and count the number of cells to 2 × 10 6 ce
lls / ml.
【0072】調製した細胞浮遊液500μl、ConA
(シグマ社)2.0μgおよび検体[本発明化合物
(a)および対照化合物(b)]の上記培地溶液250
μlをマイクロプレート(平底24穴、イワキガラス社
製)に添加し、5%CO2インキュベーターで48時間
培養した。検体の培地溶液は検体をエタノールで溶解
後、エタノールの最終濃度が0.05%になるように上
記培地溶液で希釈することにより調製した。培養後、細
胞上清液中でIL−1β量(pg/ml)をELISA
キット(アマシャム社)で測定し、IL−1β産生抑制
率(%)を求め、IC50値(μg/ml)を算出した。500 μl of the prepared cell suspension, ConA
(Sigma) 2.0 μg and the above medium solution 250 of the sample [the present compound (a) and the control compound (b)]
μl was added to a microplate (flat bottom, 24 wells, manufactured by Iwaki Glass Co., Ltd.) and cultured in a 5% CO 2 incubator for 48 hours. The medium solution of the sample was prepared by dissolving the sample in ethanol and then diluting it with the above medium solution so that the final concentration of ethanol was 0.05%. After culturing, the amount of IL-1β (pg / ml) in the cell supernatant was measured by ELISA.
It was measured with a kit (Amersham), the IL-1β production inhibition rate (%) was determined, and the IC50 value (μg / ml) was calculated.
【0073】なお、検体の濃度は0、3、10および3
0μg/mlとした。The sample concentrations were 0, 3, 10 and 3
It was set to 0 μg / ml.
【0074】その結果、本発明化合物(a)のIL−1
産生抑制作用のIC50値は13.3μg/mlと算出さ
れたが、対照化合物(b)は上記濃度においては50%
以上の抑制作用を示さず、IC50値は求められなかっ
た。As a result, the compound (a) of the present invention, IL-1
The IC50 value for the production inhibitory effect was calculated to be 13.3 μg / ml, but the control compound (b) was 50% at the above concentration.
The IC50 value could not be determined without showing the above-mentioned inhibitory action.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 柏 真理子 東京都豊島区高田3丁目24番1号 大正製 薬株式会社内 (72)発明者 畑山 勝男 東京都豊島区高田3丁目24番1号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mariko Kashiwa 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Inside Pharmaceutical Co., Ltd.
Claims (1)
リド化合物およびその塩を有効成分として含有すること
を特徴とする抗炎症剤。1. A formula An anti-inflammatory agent comprising a 5-amino-2-phenoxysulfoneanilide compound represented by and a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03268694A JP3721583B2 (en) | 1993-03-19 | 1994-03-02 | Anti-inflammatory agent |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5-60110 | 1993-03-19 | ||
JP6011093 | 1993-03-19 | ||
JP03268694A JP3721583B2 (en) | 1993-03-19 | 1994-03-02 | Anti-inflammatory agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH06321776A true JPH06321776A (en) | 1994-11-22 |
JP3721583B2 JP3721583B2 (en) | 2005-11-30 |
Family
ID=26371268
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP03268694A Expired - Fee Related JP3721583B2 (en) | 1993-03-19 | 1994-03-02 | Anti-inflammatory agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3721583B2 (en) |
-
1994
- 1994-03-02 JP JP03268694A patent/JP3721583B2/en not_active Expired - Fee Related
Also Published As
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---|---|
JP3721583B2 (en) | 2005-11-30 |
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